Anatomy and Neuroscience - Theses

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Start date: 2010 × End date: 2019 × Subject: neurodegeneration × Author: MINTER, MYLES ×

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    On type-1 interferons, neuro-inflammation and Alzheimer's disease
    MINTER, MYLES ( 2015)
    Alzheimer’s disease (AD) is the most common form of dementia worldwide. Hyper-phosphorylation of tau, leading to intracellular neurofibrillary tangles, and accumulation of the amyloid-β (Aβ) peptide, leading to formation extracellular plaques, are the two key brain proteinopathies associated with the progressive neuro-degenerative disease. To date, therapeutics targeting these pathologies have proven ineffective in the treatment of AD and highlights the need for new lines of investigation into disease mechanisms. Neuro-inflammation is evident in AD patients, comprising of enhanced gliosis surrounding Aβ deposits and pro-inflammatory cytokine load. This dysregulated innate inflammatory response is deleterious and facilitates neuro-degeneration. Identifying critical mediators controlling this neuro-inflammation will prove beneficial in developing anti-inflammatory therapies for the treatment of AD. The type-1 interferons (IFNs) are pleiotropic cytokines that control pro-inflammatory cytokine secretion and are master regulators of the innate immune response. This thesis carries the hypothesis that the type-1 IFNs play a critical role in the exacerbation of neuro-inflammation and actively contribute to the progression of AD. This thesis aimed to characterise the role of type-1 IFNs in the neuro-inflammatory response to soluble Aβ1-42 in CNS cell types, evaluate the effect of removing type-1 IFN signalling in the APPSWE/PS1ΔE9 mouse model of AD and hence identify a role for type-1 IFNs in the progression of AD. Soluble Aβ1-42 triggers a type-1 IFN neuro-inflammatory response in primary cultured neurons. Removal of type-1 IFN signalling (IFNAR1-/-) in these cultures attenuated pro-inflammatory responses to Aβ1-42 affording protection against neurotoxicity via attenuation of pro-apoptotic caspase-3 activation. The use of Myd88-/-, IRF7 and IRF3 knockdown cultures, critical in toll-like receptor-dependent signalling, identified that neurons utilise this receptor family to detect Aβ1-42 and initiate a neuro-degenerative type-1 IFN response. Primary IFNAR1-/- mixed astrocyte and microglial cultures display an attenuated type-1 IFN and pro-inflammatory cytokine response to Aβ1-42. These cultures adopt an anti-inflammatory and neuro-protective M2-like polarisation state, opposing the wildtype neuro-degenerative M1-like response to soluble Aβ1-42. To investigate the role of in vivo type-1 IFN signalling in the progression of AD, APPSWE/PS1ΔE9 mice lacking type-1 IFN signaling were generated. APPSWE/PS1ΔE9 x IFNAR1-/- were partially rescued from spatial learning and memory deficits as assessed by the Morris water maze. These mice displayed no alterations in amyloid plaque load but reduced soluble Aβ monomer concentrations were detected. The type-1 IFN response was attenuated in APPSWE/PS1ΔE9 x IFNAR1-/- mice displaying altered pro-inflammatory cytokine expression. Interestingly, cortical astrogliosis was elevated in these mice but microgliosis was attenuated. These microglial populations adopted a neuro-protective M2-like activation state, supporting our in vitro findings. Finally, a type-1 IFN signature was evident in the brains of human post-mortem AD patients Findings from this thesis identify the type-1 IFNs as key mediators of the neuro-inflammatory response in AD. This response is deleterious to disease progression and suggests that targeting type-1 IFN signalling may be therapeutically relevant for anti-inflammatory treatment of AD.